A recent FDA Safety Alert recommends in-line filtration for all TPN admixtures. Although rigid crystalline particulates can be effectively removed by in-line filters, the fate of flexible lipid droplets enlarged through electromechanical destabilization is less clear. Lipid droplets having diameters greater than 5 microns (.mu.m) could lodge in the pulmonary microvasculature and produce an embolic syndrome. Recent evidence suggests that total nutritional admixtures (TNAs) in which lipid droplets having a diameter in excess of 5 .mu.m or more constitute more than 0.4% of the final fat concentration are unstable.
On Apr. 18, 1994 the Food and Drug Administration (FDA) issued a nationwide Safety Alert reporting two deaths and at least two cases of respiratory distress that appear to have resulted from calcium phosphate precipitants present in extemporaneously prepared, lipid emulsion-containing TNAs intended for intravenous administration. To avoid similar tragedies, the FDA has requested commercial suppliers of parenteral nutrients to develop data that might eventually be used to revise relevant labeling instructions involving parenteral nutrient (PN) infusions containing calcium and phosphate salts. In addition, seven specific recommendations were made by the FDA in order to avoid the dangers associated with calcium phosphate precipitation. In particular, the FDA recommended the use of "air-eliminating filters" for all PN admixtures. Specifically, 1.2 .mu.m porosity membrane in-line filters were suggested for fat emulsion-containing PN dispersions and 0.22 .mu.m in-line filters for fat emulsion-free PN solutions. Although rigid crystalline particulates, such as dibasic calcium phosphate (CaHPO.sub.4), can be effectively removed by in-line filters, the fate of flexible lipid droplets enlarged through electromechanical destabilization is less clear. The degree of destabilization of TNAs is related to the composition of the formulation that often varies in accordance with the patient's clinical condition.
The malleable characteristics or deformability of lipid droplets, coupled with a pressurized pump infusion, may allow the passage of droplets having diameters in excess of 1.2 microns through in-line filters having a pore size of 1.2 microns in much the same way that the deformability of red blood cells allows them to pass through blood vessels, such as capillaries, that are a fraction of their size. Although abnormally large lipid droplets may maneuver through the pulmonary microvasculature, it is equally possible that the administration of sufficiently large numbers of lipid droplets having diameters greater than 5 .mu.m could produce an embolic syndrome (i.e., the equivalent of a toxic pharmacological dose). Although the precise toxic dose of enlarged fat globules from unstable TNAs is not known, if droplets having a diameter in excess of 5 microns constitute more than 0.4% of the final fat concentration, the resulting mixture is unstable and unfit for administration.
A typical parenteral infusion pump routinely used to deliver PN therapy provides infusion under pressure at values up to 10-15 pounds per square inch (PSI). Since 1 PSI is approximately equal to 50 mm Hg, these infusion pressures are 25 to 50 times higher than the usual mean pulmonary artery pressures. Such ex vivo conditions may enhance the passage of pliable, yet clinically dangerous, lipid droplets. Therefore, the study conditions presented here pose a considerable stress in the in-line filter, in terms of production of excessively large lipid droplets which might not traverse the pulmonary circulation.
Although the problem of microvascular clogging or embolic syndrome is not as prevalent for other types of emulsions for patient use, emulsions having large lipid droplets reflect an unstable admixture and may cause additional health problems. Accordingly, while the use of in-line filters described herein is most advantageous for lipid-containing parenteral nutrition admixtures, it can be used for other nutritional admixtures or other lipid containing emulsions.
An object of the invention is to provide a method for reliably reducing the number of dangerously large lipid droplets from a TNA mixture prior to intravenous administration.
A further object of the invention is to provide a method of parenteral feeding while reducing the number of large lipid droplets in the parenteral feeding admixture.
Another object of the invention is to provide a reduction in large lipid droplets in emulsions.
These and other objects and features of the invention will be apparent from the summary of the invention and the claims.